Discovered more than 50 years ago, ketamine is an anesthetic that is thought to act primarily by antagonizing the glutamatergic NMDAR (N-methyl-D-aspartate receptor). It is typically administered intramuscularly or intravenously for starting and maintaining general anesthesia in humans and other animals, and has also been used for anti-anxiety, sedation, and analgesic purposes. See, e.g., Costi et al., Curr. Behav. Neurosci. Rep. 2015, 4. 216-225; Oddo et al., Crit. Care 2016, 20, 128-138. In addition, ketamine has shown potent efficacy in treating depression and pain when administered at sub-anesthetic doses; even single infusions of such doses appear to show rapid action in treating bipolar depression and treatment-resistant major depression. Iadarola et al., Ther. Adv. Chronic Dis. 2015, 6, 97-114; Zarate et al., Arch. Gen. Psychiatry 2006, 63, 856-864; Lally et al. Transl. Psychiatry 2014, 4, e469; Murrough et al., Am. J. Psychiatry 2013, 170, 1134-1142.
Clinical use of ketamine is limited, however, by its poor oral bioavailability, abuse liability, and undesirable psychological reactions, such as dissociative effects and hallucinations observed at even low doses. See, e.g., Strayer and Nelson, Am. J. Emerg. Med. 2008, 26, 985-1028; Morgan and Curran, Addiction 2010, 107, 27-38. In addition, ketamine action is complicated by multiple metabolites arising after its administration, many of which do not have anesthetic properties. See, e.g., Leung et al., J. Med. Chem. 1986, 29, 2396-2399.
Recent studies have shown that a ketamine metabolite, (2R,6R)-hydroxynorketamine, has antidepressant activity in mice. Zanos et al., Nature 2016, 533, 481-486. In addition, hydroxynorketamine (HNK) metabolites have been implicated in the analgesic efficacy of ketamine in treating pain. Moaddel et al., Talanta 2010, 15, 1892-1904. In contrast to ketamine, HNK is not known to inhibit NMDAR, but is thought to modulate a different glutamate receptor, the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor. Furthermore, the action of HNK does not appear to be associated with undesired effects that can result from ketamine therapy, such as abuse liability and anesthetic effects.
These observations highlight the need for alternative ketamine therapeutics useful in treating depression, pain, and other CNS disorders. The present disclosure meets these and other needs in the art by disclosing chemical entities, including compounds, which can act through HNK-mediated pathways.